The objective of this proposal is to understand the molecular basis of optic atrophy due to mitochondria dysfunction. Mitochondria are major producers of both cellular energy (via oxidative phosphorylation; OXPHOS), and toxic reactive oxygen species (ROS). OXPHOS impairment can result in a cellular energy deficiency and increased ROS production. Numerous clinical studies as well as cellular and animal models of bioenergetic disease have suggested that the neural retina and optic nerve are highly sensitive to OXPHOS perturbation and oxidative stress. Hence, ophthalmic disease, and optic atrophy in particular, is perhaps the most common clinical expression of mitochondrial dysfunction. Leber's Hereditary Optic Neuropathy (LHON), for example, is the most common disease due to mitochondrial DNA (mtDNA) missense mutations. LHON patients exhibit optic atrophy due to degeneration of the retinal ganglion cells, followed by optic nerve degeneration. Autosomal dominant optic (DOA) atrophy shares clinical and neuropathologic features with LHON. Very recently, the gene for the most common form of DOA, OPA1, has been mapped and sequenced. Mutant OPA1 protein is localized to the mitochondria and results in a disruption of mitochondrial morphology. [unreadable] [unreadable] Although pathophysiological mechanisms of LHON and DOA converge in the mitochondria, the underlying molecular basis for these mitochondrial optic atrophies remains unknown. We hypothesize that both LHON and DOA result from a vicious cycle of bioenergetic insufficiency, increased mitochondrial ROS generation, and subsequent apoptosis. We propose to test this hypothesis with three Specific Aims: (1) genetic analysis, with special emphasis on the role of nDNA and mtDNA modifiers of LHON expression; (2) investigation of the type and magnitude of OXPHOS defects, ROS generation, and apoptosis; and (3) study of global gene expression/metabolic pathway patterns. We expect that this type of comprehensive analysis will allow insights into both common and disease-specific mitochondrial-mediated mechanisms responsible for the mitochondrial optic atrophies, facilitating the development of effective therapies, where none currently exists.